Macrophage respiratory supercomplexes and metabolic reprogramming upon anti-bacterial immunity

Tioli, Gaia (2021) Macrophage respiratory supercomplexes and metabolic reprogramming upon anti-bacterial immunity, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Scienze biomediche e neuromotorie, 34 Ciclo.
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Metabolic reprogramming has recently emerged as a major feature of innate immune cells upon bacterial infection. At the core of this physiological process is the mitochondrion, a bioenergetic organelle that also serves as an immune signaling platform. The dynamic supramolecular organization of the mitochondria electron transport system (ETS) complexes forming the respiratory supercomplexes (SCs) may confer functional advantages to mitochondria. However, the precise role of SCs in metabolic adaptations in immune host defense remains to be determined. Indications exist that organizational and functional adaptations occur in the ETS of macrophages to allow metabolic plasticity during engulfment of live Gram-¬negative bacteria (e.g. E. coli). Furthermore, several groups demonstrated that the tricarboxylic acid cycle (or Krebs cycle) of macrophages stimulated with the Toll-like receptor 4 ligand lipopolysaccharides – the main component of Gram- cell wall – shows two breakpoints at the isocitrate dehydrogenase and at the succinate dehydrogenase (SDH/Complex II). Previous experiments suggested the involvement of Complex II in macrophages metabolic reprogramming, depending on the microbial stimulus. In this work we investigated whether mitochondrial reprogramming depends on the nature of the bacteria encountered and how this in turn modulates innate immune outcomes. Our data show that the sensing of Gram- and Gram+ bacteria by macrophages differentially regulates mitochondrial oxygen consumption rate, mitochondrial ATP synthesis and respiratory CII activity throughout the time of infection. Metabolomics analysis of bacteria-treated macrophages show distinct reprogramming of the Krebs cycle induced by Gram- and Gram+ bacteria. We thus investigated whether the pharmacological manipulation of fumarate/α-ketoglutarate ratio and SDH/CII activity modulate pro- and anti-inflammatory cytokines production in vitro and in vivo. Our preliminary results indicate that there is no significant difference in mitochondrial respiration capacity and ATP production induced by CII inhibitors, which suggest possible compensatory effects mediated by SCs and the other dehydrogenases composing the mitochondrial ETS.

Tipologia del documento
Tesi di dottorato
Tioli, Gaia
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
innate immunity, macrophages, mitochondria, supercomplexes
Data di discussione
25 Novembre 2021

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